bcl-2 and c-myc Expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase

Handa, Hiroshi; Hegde, Uprendra P.; Kotelnikov, Valery M.; Mundle, Suneel; Dong, Liming; Burke, P.; Rose, Sheldon; Gaskin, Fred; Raza, A.; Preisler, Harvey D.

doi:10.1016/s0145-2126(97)00006-4

Cited by 41 publications

(32 citation statements)

References 23 publications

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“…It is noteworthy that K562 derives from chronic myeloid leukemia, where it has been reported higher MYC expression in final blast crisis phase of the disease (Handa et al, 1997;Beck et al, 1998 and our unpublished results). Alterations of TP53 are infrequent in this disease and therefore our results support the idea that deregulated MYC contributes to tumor progression in this leukemia through impairment of p53 function.…”

Section: Myc and P53 Antagonism: Implications In Tumorigenesissupporting

confidence: 56%

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

et al. 2005

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We have previously demonstrated that c-Myc impairs p53-mediated apoptosis in K562 human leukemia cells, which lack ARF. To investigate the mechanisms by which c-Myc protects from p53-mediated apoptosis, we used K562 cells that conditionally express c-Myc and harbor a temperature-sensitive allele of p53. Gene expression profiles of cells expressing wild-type conformation p53 in the presence of either uninduced or induced c-Myc were analysed by cDNA microarrays. The results show that multiple p53 target genes are downregulated when c-Myc is present, including p21 WAF1 , MDM2, PERP, NOXA, GADD45, DDB2, PIR121 and p53R2. Also, a number of genes that are upregulated by c-Myc in cells expressing wild-type conformation p53 encode chaperones related to cell death protection as HSP105, HSP90 and HSP27. Both downregulation of p53 target genes and upregulation of chaperones could explain the inhibition of apoptosis observed in K562 cells with ectopic c-Myc. Myc-mediated impairment of p53 transactivation was not restricted to K562 cells, but it was reproduced in a panel of human cancer cell lines derived from different tissues. Our data suggest that elevated levels of Myc counteract p53 activity in human tumor cells that lack ARF. This mechanism could contribute to explain the c-Myc deregulation frequently found in cancer.

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Section: Myc and P53 Antagonism: Implications In Tumorigenesissupporting

confidence: 56%

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

et al. 2005

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“…c-MYC appears to play a role in BCR-ABL-mediated transformation 30,[152][153][154][155] and may mediate its effects either by antagonising the function of p53 156,157 or by acting as a co-operative oncogene with the BCR-ABL. 154 MYC expression is normal in chronic phase CML but is increased in patients with blast crisis.…”

Section: Activation Of Oncogenesmentioning

confidence: 99%

“…154 MYC expression is normal in chronic phase CML but is increased in patients with blast crisis. 116,155 Overexpression of c-MYC occurs as a result of increased transcription 156 or trisomy 8 158 frequently observed during disease progression or stabilization of c-MYC m-RNA due to polyadenylation. 117 Additional translocations like t(3;21) have been reported in high frequency in blast crisis.…”

Section: Activation Of Oncogenesmentioning

confidence: 99%

Chronic myelogenous leukemia: mechanisms underlying disease progression

2002

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Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABLmediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed as increased oncogenic activity or loss of tumor suppressor activity. However, what causes transformation and disease progression to blast crisis is only poorly understood. This is in part due to the lack of a good in vivo model of chronic phase CML even though animal models developed over the last few years have started to provide insights into blast crisis development. Thus, additional in vitro and in vivo studies will be needed to provide a complete understanding of the contribution of BCR-ABL and other genes to disease progression and to improve therapeutic approaches for blast crisis CML.

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“…Alterations of p53 are very rare in the chronic phase of CML, and they occur with frequencies ranging 10 ± 25% of the blast crisis cases (Ahuja et al, 1991;Prokocimer and Rotter, 1994;Nakai and Misawas, 1995;Stuppia et al, 1997) although this frequency may be much lower, depending on the population analysed (Peller et al, 1998). Interestingly, c-myc expression is higher in cells derived from blast crisis CML than from the chronic phase (Preisler et al, 1990;Handa et al, 1997), and recent reports indicate a positive correlation of c-myc ampli®cation with progression to blast crisis (Beck et al, 1998;Jennings and Mills, 1998). Moreover, the presence of an extra allele of c-myc (chromosome 8 trisomy) is the most common karyotypic alteration in CML blast crisis (46% of cases) (Alimena et al, 1987).…”

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confidence: 99%

c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells

et al. 2000

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c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two di erent methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53 Vall35 mutant, which adopts a wild-type conformation at 328C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc signi®cantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21 WAF1 , Bax and cytomegalovirus promoters. The impairment of p21 WAF1 transactivation by c-Myc was con®rmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21 WAF1 mRNA protein were signi®cantly reduced by cMyc, while Bax levels were una ected. Consistently, cMyc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation. These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for the frequently observed deregulation of c-myc in human cancer.

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bcl-2 and c-myc Expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase

Cited by 41 publications

References 23 publications

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes

Chronic myelogenous leukemia: mechanisms underlying disease progression

c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells

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